Wolfram syndrome-associated mutations lead to instability and proteasomal degradation of wolframin

FEBS Lett. 2006 Jul 10;580(16):4000-4. doi: 10.1016/j.febslet.2006.06.036. Epub 2006 Jun 22.


Wolfram syndrome is caused by mutations in WFS1 encoding wolframin, a polytopic membrane protein of the endoplasmic reticulum. Here, we investigated the molecular pathomechanisms of four missense and two truncating mutations in WFS1. Expression in COS-7 cells as well as direct analysis of patient cells revealed that WFS1 mutations lead to drastically reduced steady-state levels of wolframin. All mutations resulted in highly unstable proteins which were delivered to proteasomal degradation. No wolframin aggregates were found in patient cells suggesting that Wolfram syndrome is not a disease of protein aggregation. Rather, WFS1 mutations cause loss-of-function by cellular depletion of wolframin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cells, Cultured
  • Chlorocebus aethiops
  • Fibroblasts / cytology
  • Fibroblasts / pathology
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mutation, Missense / genetics*
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Processing, Post-Translational*
  • Protein Structure, Quaternary
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Thermodynamics*
  • Wolfram Syndrome / genetics*


  • Membrane Proteins
  • RNA, Messenger
  • wolframin protein
  • Proteasome Endopeptidase Complex